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G pro پروتئین جی
The document provides an extensive overview of G-protein coupled receptors (GPCRs) and their signaling mechanisms, detailing the structure and function of various G-protein subunits (α, β, γ). It describes how GPCRs activate intracellular signaling pathways through the exchange of GDP for GTP, leading to effects such as modulation of ion channels and activation of downstream enzymes like adenylate cyclase and phospholipase C. Additionally, the document lists examples of ligands and physiological roles associated with different types of GPCRs and their corresponding G-protein subunits.
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G pro پروتئین جی
- 2.
- 3. Ion Channel LinkedReceptor Enzye Linked Receptor G-Protein Coupled Receptor
- 4.
- 5. • Large G-Proteins(Heterotrimeric G Proteins) • In G protein-coupled receptors (GPCR) • 3 Subunits : α, β, γ • Small G-Proteins (Momomeric G Protein) • Subunit : α
- 6. GPCR or GPLR (Gprotein coupled receptors) (G protein linked receptors) • seven-transmembrane domain receptors (7TM receptors) • heptahelical receptors • serpentine receptor
- 7. Binding ligand Changing conformation of GPCR Acting GPCR as GEF (guanine nucleotide exchange factor )
- 8. Exchanging GDPfor a GTP (inside the cell) & Activating G protein Dissociating the subunit α binding GTP from β & γ subunits
- 9. Affecting subunitα to intracellular signaling proteins(Effect Protein) or target functional proteins directly (finally a cascade) depending on the α subunit type
- 10. Pathways : ChangingPolarization of membrane by Activating or Inactivating chanells. cAMP IP3 & DAG
- 13. Types of αsubunit : • Gi/o • Gz (αi, αo) (αz) Inhibition of Adenylate Cyclase Change K+-channels gating Change Ca2+-channels gating Inhibition of Adenylate Cyclase & Activation of phosphodiesterase (PDE)
- 14. Types of αsubunit : • Gi/o (αi, αo) Inhibition of Adenylate Cyclase Change K+-channels gating Change Ca2+-channels gating
- 16. Some example ofthese receptors : • NEP ( α2 receptor) • Somatostatin (GHRIH) • PIH (Prolactin Inhibiting H.) • Histamin (H3,H4 Receptor) • Acetylcholine M2 & M4 receptors • Dopamine D2, D3, D4 receptors • GABA receptors • Prostaglandin receptors • Serotonin receptors
- 17. Types of αsubunit : • Gz (αz) Inhibition of Adenylate Cyclase & Activation of phosphodiesterase (PDE)
- 18. Types of αsubunit : • Gs • Golf • Gt • Ggust (αstimulatory) (αolfactory) (αtransdusin) (αgastdusin) Activation of Adenylate Cyclase
- 19. Types of αsubunit : • Gs (αstimulatory) Activation of Adenylate Cyclase
- 20. Some example ofthese receptors : • Glucagon • ADH (Kidney receptor) • LH & FSH • Histamin (H2 Receptor) • NEP (B1-Adrenergic receptor) • CRH (Corticotropin(ACTH) RH receptors) • ACTH receptors • GHRH • Dopamine receptors (D1 & D5) • Calcitonin receptors • Secretin receptors • Thyrotropin (TSH) receptors • Prostaglandin receptors • Prostacyclin receptors • Parathyroid (PTH) receptors • Melanocortin receptors
- 21. protein kinase A(PKA) Phosphorilation ADH : Promotes water retention by the kidneys GHRH & GHRIH : Stimulates & inhibits the synthesis and release of GH CRH : Stimulates the synthesis and release of ACTH ACTH : Stimulates the synthesis and release of Cortisol TSH : Stimulates the synthesis and release of a majorityof T4 Glucagon : Stimulates glycogen breakdown LH & FSH : Stimulates follicular maturation and ovulation Calcitonin : Decreases blood calcium levels PTH & Calcitonin : Increasing & Decreases blood calcium levels Glucagon : Stimulates lipogenesis Glucagon : Stimulates Insulin synthesis
- 22. Types of αsubunit : • Go • Gt • Ggust (αolfactory) (αtransdusin) (αgastdusin) Activation of AC
- 25. Types of αsubunit : • Gq • G12/13 (αq , α11 , α14 , α15 , α16 ) (α12, α13) Activation of PhosphoLipase C (PLC) Activation of Rho family of GTPases
- 26. Some example ofthese receptors : • NEP ( α1 receptor) • TRH receptors • GnRH receptors • Vasopressin (ADH in all organ except kidney receptors) • Histamin (H1 receptor) • Acetylcholine M1, M3, M5 muscarinic receptors • Angiotensin II receptor (type 1) • Calcitonin receptor
- 27. Gq ► Effectorprotein : Phospholipase C (PLC) Cleavege membrane Phosphoinositol (PIP2) DAG IP3 Activation of protein kinase C Release of intracellular Ca2+ Regulation of other enzymes (by protein phosphorylation) Regulation of other enzymes (by Ca2+) Vasopressin (ADH) : Induces vasoconstriction TSH : Induces the synthesis and release of a small amount of T4 Angiotensin II : Induces Aldosterone synthesis and release TRH : Induces the synthesis and release of TSH GnRH : Induces the synthesis and release of FSH and LH
- 29. G12/13 ► Effectorprotein : Rho Protein (specially in Fibroblasts) Activating Rho protein Various action e.g. : • Polimerization microtubule & microfilament (Actin) • Remoding Sytoskeleton & Changing cell shape (& regulating cell migration, phagocytosis,…) • Function in cell cycle (mitosis & cytokinesis) • Controling cell polarity • Vesicular trafficking • Apoptosis • Wound healing ▼
- 30. G βγ (Beta-gammacomplex) • Inhibition of the Gα subunit • Activate G protein coupled Inward-Rectifying Potassium Channels (Kir, GIRK) • Activation of PLA2 when bound to histamine receptors • Activating PLC, as a minor mechanism of GHRH • Activation L-type calcium channels
- 31. light-sensitive compounds (vision) Odors(olfactory substance) Taste (Gustducin substance) Pheromones Hormones Neurotransmitters etc.
- 32. -Inherent GTPaseactivity of G-protein Slow GTP hydrolasis capability of Gα associating Gβγ Allostrically Exchanging GTP/GDP -Regulator of G protein signalling (RGS) or GTPase-activating proteins (GAP) -GAP activity of Effector (PLC or AC)
- 33. Small G Protein •Small protein (20-kDa to 25-kDa) • binding to guanosine triphosphate (GTP) = activation • homologous to Ras GTPases (also called the Ras superfamily GTPases)
- 34. • Regulating metabolicenzymes • Regulating ion channels & transporters • Controlling transcription • Controlling motility & contractility • Controlling secretion • Systemic Regulating : • Embryonic development • Learning and memory • homeostasis
- 35. • Diabetes • Blindness •Allergies • Depression • Cardiovascular defects • certain forms of Cancer • In some disease Like : Cholera
- 36. Product by : 3yyedmoh3n sadatinejad
Editor's Notes
- #3 GTP-Binding Protein is wrong becouse some time it is GDP -Binding
- #4 Speak about GPLR in futur
- #5 With Techer last session Explanation & what you know
- #6 Alpha . Functional subunit & binding to GTP G proteins belong to the larger group of enzymes called GTPases α), beta (β), and gamma (γ) . There are also "small" G proteins (20-25kDa) that belong to the Ras superfamily of small GTPases. These proteins are homologous to the alpha (α) subunit found in heterotrimers, and are in fact monomeric. However, they also bind GTP and GDP and are involved in signal transduction.
- #8 Binding ligand to a domain located outside the cell the GEF domain, in turn, allosterically activates the G-protein by facilitating the exchange of a molecule of GDP for GTP at the G-protein's α-subunit ----------------- The G protein-coupled receptor kinases (GRKs) are protein kinases that phosphorylate only active GPCRs. Phosphorylation of the receptor can have two consequences: 1.Translocation: The receptor is, along with the part of the membrane it is embedded in, brought to the inside of the cell, where it is dephosphorylated within the acidic vesicular environment[39] and then brought back. This mechanism is used to regulate long-term exposure, for example, to a hormone, by allowing resensitisation to follow desensitisation. Alternatively, the receptor may undergo lysozomal degradation, or remain internalised, where it is thought to participate in the initiation of signalling events, the nature of which depend on the internalised vesicle's subcellular localisation.[38] 2.Arrestin linking: The phosphorylated receptor can be linked to arrestin molecules that prevent it from binding (and activating) G proteins, effectively switching it off for a short period of time. This mechanism is used, for example, withrhodopsin in retina cells to compensate for exposure to bright light. In many cases, arrestin binding to the receptor is a prerequisite for translocation. For example, beta-arrestin bound to β2-adrenoreceptors acts as an adaptor for binding with clathrin, and with the beta-subunit of AP2 (clathrin adaptor molecules); thus the arrestin here acts as a scaffold assembling the components needed for clathrin-mediated endocytosis of β2-adrenoreceptor
- #9 Binding ligand to a domain located outside the cell the GEF domain, in turn, allosterically activates the G-protein by facilitating the exchange of a molecule of GDP for GTP at the G-protein's α-subunit ----------------- The G protein-coupled receptor kinases (GRKs) are protein kinases that phosphorylate only active GPCRs. Phosphorylation of the receptor can have two consequences: 1.Translocation: The receptor is, along with the part of the membrane it is embedded in, brought to the inside of the cell, where it is dephosphorylated within the acidic vesicular environment[39] and then brought back. This mechanism is used to regulate long-term exposure, for example, to a hormone, by allowing resensitisation to follow desensitisation. Alternatively, the receptor may undergo lysozomal degradation, or remain internalised, where it is thought to participate in the initiation of signalling events, the nature of which depend on the internalised vesicle's subcellular localisation.[38] 2.Arrestin linking: The phosphorylated receptor can be linked to arrestin molecules that prevent it from binding (and activating) G proteins, effectively switching it off for a short period of time. This mechanism is used, for example, withrhodopsin in retina cells to compensate for exposure to bright light. In many cases, arrestin binding to the receptor is a prerequisite for translocation. For example, beta-arrestin bound to β2-adrenoreceptors acts as an adaptor for binding with clathrin, and with the beta-subunit of AP2 (clathrin adaptor molecules); thus the arrestin here acts as a scaffold assembling the components needed for clathrin-mediated endocytosis of β2-adrenoreceptor
- #10 Ophen this 2 path ways
- #11 Ophen this 2 path ways
- #14 Dicrease c AMP----opening k+ channels by beta,gamma subunit Inhibitory.other.zeta
- #15 Dicrease c AMP----opening k+ channels by beta,gamma subunit Inhibitory.other.zeta Opening K+-channels Closing Ca2+-channels
- #18 Dicrease c AMP----opening k+ channels by beta,gamma subunit Inhibitory.other.zeta
- #19 Increase cAMP
- #20 Increase cAMP
- #21 EP & NEP
- #22 Effector Pro : Adenilat Cyclase PKA is also known as cAMP-dependent protein kinase Gi:Dicrease cAMP :NEP (alpha2 receptor),somatostatin(GHRIH),PIH, Histamin (H3,H4 Receptor), Acetylcholine M2 & M4 receptors, Dopamine D2, D3, D4,GABAB receptor, Prostaglandin EP1, EP3, FP, & TP receptors Gs:Increase CAMP : glucagon.ADH.LH.FSH. Histamin (H2 Receptor),NEP (B1-Adrenergic receptor),CRH,GHRH
- #23 Dicrease c AMP----opening k+ channels by beta,gamma subunit Inhibitory.other.zeta Rhodopsin Taste receptors
- #26 Rho is Ras homologus gene The members of the Rho GTPase family have been shown to regulate many aspects of intracellular actin dynamics, and are found in all eukaryotic organisms including yeasts and some plants. Three members of the family have been studied a great deal: Cdc42, Rac1, and RhoA. Rho proteins have been described as "molecular switches" and play a role in cell proliferation,apoptosis, gene expression, and multiple other common cellular functions
- #28 IP3: TRH,GnRH.Vasopressin,NEP(alpha 1 receptor),Histamin(H1 receptor) IP3 acts on IP3 receptors found in the membrane of the endoplasmic reticulum (ER) to elicit Ca2+release from the ER, while DAG diffuses along the plasma membrane where it may activate any membrane localized forms of a second ser/thr kinase called Protein Kinase C (PKC)
- #30 Regulators Apoptose-changing conformation cause to flip flop plc(cholin) to pls(serin) Three general classes of regulators of rho protein signaling have been identified: guanine nucleotide exchange factor (GEFs), GTPase-activating proteins (GAPs) and guanine nucleotide dissociation inhibitors (GDIs)[8]. GEFs control the release of GDP from the rho protein and the replacement with GTP. GAPs control the ability of the GTPase to hydrolyze GTP to GDP, controlling the natural rate of movement from the active conformation to the inactive conformation. GDI proteins form a large complex with the rho protein helping to prevent diffusion within the membrane and into the cytosol, thus acting as an anchor and allowing for very specific spatial control of rho activation[8]. --- Ligand that cause this changes like FGF,WNT,… (Embriogenesis) ----- Cellular shape for example : Mental retardation is because of malfunction of dendritic spine may be result of disorder in rho protein ------------ Cancer : malfunction of rho protein. Increaseing mitosis,
- #31 Regulators Apoptose-changing conformation cause to flip flop plc(cholin) to pls(serin) Three general classes of regulators of rho protein signaling have been identified: guanine nucleotide exchange factor (GEFs), GTPase-activating proteins (GAPs) and guanine nucleotide dissociation inhibitors (GDIs)[8]. GEFs control the release of GDP from the rho protein and the replacement with GTP. GAPs control the ability of the GTPase to hydrolyze GTP to GDP, controlling the natural rate of movement from the active conformation to the inactive conformation. GDI proteins form a large complex with the rho protein helping to prevent diffusion within the membrane and into the cytosol, thus acting as an anchor and allowing for very specific spatial control of rho activation[8]. --- Ligand that cause this changes like FGF,WNT,… (Embriogenesis) ----- Cellular shape for example : Mental retardation is because of malfunction of dendritic spine may be result of disorder in rho protein ------------ Cancer : malfunction of rho protein. Increaseing mitosis,
- #32 The ligands that bind and activate these receptors include light-sensitive compounds, odors, pheromones, hormones, andneurotransmitters, and vary in size from small molecules topeptides to large proteins light and olfactory stimulatory molecules);adenosine, bombesin, bradykinin, endothelin, γ-aminobutyric acid (GABA), hepatocyte growth factor (HGF), melanocortins, neuropeptide Y, opioid peptides,opsins, somatostatin, GH, tachykinins, members of thevasoactive intestinal peptide family, and vasopressin;biogenic amines (e.g., dopamine, epinephrine,norepinephrine, histamine, glutamate (metabotropiceffect), glucagon, acetylcholine (muscarinic effect), andserotonin); chemokines; lipid mediators of inflammation(e.g., prostaglandins, prostanoids, platelet-activating factor, and leukotrienes); and peptide hormones (e.g.,calcitonin, C5a anaphylatoxin, follicle-stimulating hormone (FSH), gonadotropin-releasing hormone (GnRH), neurokinin, thyrotropin-releasing hormone (TRH), and oxytocin GPCRs that act as receptors for stimuli that have not yet been identified are known as orphan receptors.
- #33 Exchanging GTP/GDP & reassociat alpha subunit to gamma beta subunit GAP activity of Effector in Gq family (PLC) Lipidation In order to associate with the inner leaflet of the plasma membrane, many G proteins and small GTPases are lipidated, that is, covalently modified with lipid extensions. They may be myristolated, palmitoylated or prenylated. میدانیم پروتینهای غشایی در سه دسته تقسیم بندی میشوند. دسته اول پروتئینهای اینتگرال .دسته دوم پروتئین های پریفرال.و نهایتا دسته سوم پروتئینهای لنگر انداخته به لیپید که خود به سه گروه تقسیم می شوند : ۱. اتصال یافته به سطح سیتوزولی غشای پلاسما توسط میریستات (myristate ) ۲. اتصال یافته به سطح سیتوزولی غشای پلاسما توسط فارنیسیل (farnesyl ) ۳. اتصال یافته به سطح خارج سلولی غشای پلاسما توسط گلیکوزیل فسفاتیدیل اینوزیتول شکل 2-F-6 . نمایشی از anchor ها که توسط برخی پروتئین ها به غشای پلاسمایی متصل شده اند. v-Src نوعی از پروتئین تیروزین کیناز غیر وابسته به رسپتور می باشد که شامل سیگنال دهی سلول می شود. پروتئین Ras نقش مهمی را در سیگنال دهی سلولی ایفا می کند.
- #34 Small GTPases are a family of hydrolase enzymes that can bind and hydrolyze guanosine triphosphate (GTP). They are a form of G-proteins found in the cytosol which are homologous to the alpha subunit of heterotrimeric G-proteins, but unlike the alpha subunit of G proteins, a small GTPase can function independently as a hydrolase enzyme to bind to and hydrolyze a guanosine triphosphate (GTP) to form guanosine diphosphate (GDP). The most well-known members are the Ras GTPases and hence they are sometimes called Ras superfamily GTPases.
- #35 G proteins regulate metabolic enzymes, ion channels, transporters, and other parts of the cell machinery, controlling transcription, motility, contractility, and secretion, which in turn regulate systemic functions such as embryonic development, learning and memory, and homeostasis
- #36 G proteins are important signal transducing molecules in cells. "Malfunction of GPCR [G Protein-Coupled Receptor] signaling pathways are involved in many diseases, such as diabetes, blindness, allergies, depression, cardiovascular defects, and certain forms of cancer. It is estimated that more than half of the modern drugs' cellular targets are GPCRs